In 1983, ranitidine received approval from the US FDA. By 1988 ranitidine had become the world's best-selling drug with annual sales of $1 billion. In the year 2004, in the US ranitidine even got FDA approval as an OTC.
Now to go back a little, since the 1980’s there have been publications in clinical, epidemiological, environmental, and other publications on N-nitrosodimethylamine (NDMA), and its possible association with certain cancers.
The ICH M7(R1) guideline sets out principles for determining acceptable limits for mutagenic / DNA reactive impurities.
The pharmacovigilance system was established by the US FDA and EMA more than a couple of decades back. Global literature search and its incorporation into risk management was part of the system. Signal detection and its management became an acceptable part of the science of risk management. Regulators did not fall short of introducing guidelines on market authorization holders' responsibilities for risk identification and management.
By quarter 3 of 2019, the U.S. and European regulators had started reviewing the safety of ranitidine. At a similar timeframe, Emery Pharma filed a Citizen Petition with the FDA regarding ranitidine, excess NDMA exposure, and the possible increased risk of certain cancers.
It does not seem entirely surprising that since the association of ranitidine, NDMA and safety concerns of excess NDMA became more common public knowledge, there was a substantial increase in research work resulting in successful publications. The objective of these studies seemed to elucidate the negative effect of high-temperature storage on the stability of ranitidine with respect to the potential formation of NDMA or establish through some kind of kinetic human studies that ranitidine is not or unlikely to be converted to NDMA in a general population or that the excess of NDMA generated could be compared to the NDMA generally available in certain processed meat food.
More than twenty years after the main ranitidine patent expired, in November 2019 the US FDA issued a statement “Investigations take time”. That brings in the long ongoing risk assessment of ‘Sartans’, in the light of NDMA impurities.
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